TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

Nobuaki Takahashi, Sayaka Hamada-Nakahara, Yuzuru Itoh, Kazuhiro Takemura, Atsushi Shimada, Yoshifumi Ueda, Manabu Kitamata, Rei Matsuoka, Kyoko Hanawa-Suetsugu, Yosuke Senju, Masayuki X. Mori, Shigeki Kiyonaka, Daisuke Kohda, Akio Kitao (), Yasuo Mori () and Shiro Suetsugu ()
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Nobuaki Takahashi: Laboratory of Molecular Biology, Graduate School of Engineering, and Laboratory of Environmental Systems Biology, Hall of Global Environmental Studies, Kyoto University
Sayaka Hamada-Nakahara: Laboratory of Membrane and Cytoskeleton Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo
Yuzuru Itoh: Laboratory of Membrane and Cytoskeleton Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo
Kazuhiro Takemura: Laboratory of Computational Protein Science, Institute of Molecular and Cellular Biosciences, University of Tokyo
Atsushi Shimada: Medical Institute of Bioregulation, Kyushu University
Yoshifumi Ueda: Laboratory of Molecular Biology, Graduate School of Engineering, and Laboratory of Environmental Systems Biology, Hall of Global Environmental Studies, Kyoto University
Manabu Kitamata: Laboratory of Membrane and Cytoskeleton Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo
Rei Matsuoka: Medical Institute of Bioregulation, Kyushu University
Kyoko Hanawa-Suetsugu: Laboratory of Membrane and Cytoskeleton Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo
Yosuke Senju: Laboratory of Membrane and Cytoskeleton Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo
Masayuki X. Mori: Laboratory of Molecular Biology, Graduate School of Engineering, and Laboratory of Environmental Systems Biology, Hall of Global Environmental Studies, Kyoto University
Shigeki Kiyonaka: Laboratory of Molecular Biology, Graduate School of Engineering, and Laboratory of Environmental Systems Biology, Hall of Global Environmental Studies, Kyoto University
Daisuke Kohda: Medical Institute of Bioregulation, Kyushu University
Akio Kitao: Laboratory of Computational Protein Science, Institute of Molecular and Cellular Biosciences, University of Tokyo
Yasuo Mori: Laboratory of Molecular Biology, Graduate School of Engineering, and Laboratory of Environmental Systems Biology, Hall of Global Environmental Studies, Kyoto University
Shiro Suetsugu: Laboratory of Membrane and Cytoskeleton Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: Abstract Mutations in the ankyrin repeat domain (ARD) of TRPV4 are responsible for several channelopathies, including Charcot–Marie–Tooth disease type 2C and congenital distal and scapuloperoneal spinal muscular atrophy. However, the molecular pathogenesis mediated by these mutations remains elusive, mainly due to limited understanding of the TRPV4 ARD function. Here we show that phosphoinositide binding to the TRPV4 ARD leads to suppression of the channel activity. Among the phosphoinositides, phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) most potently binds to the TRPV4 ARD. The crystal structure of the TRPV4 ARD in complex with inositol-1,4,5-trisphosphate, the head-group of PI(4,5)P2, and the molecular-dynamics simulations revealed the PI(4,5)P2-binding amino-acid residues. The TRPV4 channel activities were increased by titration or hydrolysis of membrane PI(4,5)P2. Notably, disease-associated TRPV4 mutations that cause a gain-of-function phenotype abolished PI(4,5)P2 binding and PI(4,5)P2 sensitivity. These findings identify TRPV4 ARD as a lipid-binding domain in which interactions with PI(4,5)P2 normalize the channel activity in TRPV4.

Date: 2014
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DOI: 10.1038/ncomms5994

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